Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 World Health Organization...
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Transcript of Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 World Health Organization...
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 1
World Health OrganizationTraining Workshop on Pharmaceutical
Quality, Good Manufacturing Practice & Bioequivalence
Planning a BE Study
Kiev, October 3 – 7, 2005
Dr. H. Potthast ([email protected])
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 2
Guidance DocumentsGuidance Documents
EU “Note for Guidance on the Investigation ofBioavailability and Bioequivalence”CPMP/EWP/QWP/1401/98 and related guidances and documents (www.emea.eu.int/pdfs/human/ewp )
FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000)
Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992
related guidances and current scientific discussion
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 3
DefinitionsDefinitions
Bioavailability – rate and extent at which a drug substance... becomes available in the general system (product characteristic!)
Bioequivalence – equivalent bioavailability within pre-set acceptance ranges
Pharmaceutical equivalence Bioequivalence
Bioequivalence Therapeutic equivalence
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 4
DefinitionsDefinitions
♦ „Two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives AND if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same.“
[section 2.4 of the EU guidance on BA and BE]
possible surrogate for full clinical/toxicological documentation
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 5
DefinitionsDefinitions
♦ „A generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.“
[new EU Directive 2004/27/EC: Art. 10.1]
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 6
DefinitionsDefinitions
♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.
[Faassen et al. Clin Pharmacokinet 43 (2004)1117]
what does the product do to the drug substance?
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 7
BE ObjectivesBE Objectives
Bioequivalence Studies
in vivo comparison by means of volunteers serving as in vivo dissolution model
‘biological quality control’
comparison of product characteristics in order to ensure therapeutic equivalence
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 8
Choice of DesignChoice of Design
Single-dose Studies
usually for IR drug products
Multiple-dose/steady-state Studies usually for MR drug products in addition to single-dose
studies dose/time dependent pharmacokinetics (mainly BA
studies!) possible analytical problems
variability issues
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 9
Study ProtocolStudy Protocol
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 10
Study ProtocolStudy Protocol
♦ „A document that describes the objective(s), design, methodology, statistical consideration and organisation of a trial. It usually gives the background and rationale of the trial …“Ref.: ICH GCP Guidance
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 11
Study ProtocolStudy Protocol
General Information/Title Page- Title- Protocol Number- Version Number/Date- Sponsor Details
- Name, Address, Telephone- Monitor/Medical Personnel
- Investigator Details- Principal Investigation, Medical Doctor
- Other Laboratory/Institution Details
Responsibilities!
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 12
Ethical ConsiderationsEthical Considerations
IEC / IRB: ICH Definition
An independent body of medical, scientific and non-scientific members
Responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by,
Among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects;
Independent “Risk-benefit” evalution
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 13
Ethical ConsiderationsEthical Considerations
Composition requirements ICH GCP At least 5 members At least one member whose primary area of interest
is a non-scientific area At least one member who is independent of the trial
site Members without conflicting interest
Only those members independent of the investigator and the sponsor should review on a trial-related matter
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 14
Ethical Ethical CConsiderationsonsiderations
Additional US FDA requirement for IRB composition:
Diverse backgrounds (race, gender, cultural, qualification)
Not entirely one gender Special expertise may be invited but without voting
rights
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 15
Ethical ConsiderationsEthical Considerations
Required documents
Protocol (signed at least by the principal investigator) Patient Information Sheet/Consent Form Investigator´s Brochure Subject recruitement procedures (e. g.
advertisements)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 16
Ethical ConsiderationsEthical Considerations
Approval notification to Investigator Timely written approval
- Identification of study (title, protocol number, version, investigator, site)
- Specify all items reviewed- Date & place of review- Trial/study related decisions- Reasons for modifications & disapprovals
Minimum information required by ICH-GCP: Date of the meeting Documents reviewed (versions & dates) List of members
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 17
Study ProtocolStudy Protocol
Protocol Development
Definition of Responsibilities
Organisation, premises, personnel & QMS Clinical phase Bioanalytical phase Statistics and reporting Archival
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 18
Protocol DevelopmentProtocol Development
Drug substance / Drug products
Knowledge of Particularities e.g. pharmacokinetics (t1/2, peak concentration, metabolism…) important side effects (acceptable for healthy volunteers?) practicability of roughly anticipated measurement
period and/or wash-out period (crossover study possible?) concept of bioanalytical method available? plasma concentrations sufficiently quantifiable
(administration of more than one dosage form necessary?)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 19
Protocol DevelopmentProtocol Development
Drug Products Availability Certification
Content In vitro dissolution
Preparation of investigative products per volunteer acc. to GMP
Protocol amendment for product details frequently necessary (e. g. labeling)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 20
Study SubjectsStudy Subjects
Selection of subjects♦ description of volunteers; smoker, vegetarian,
phenotyping…. ♦ Verifying health of volunteers ( e. g. ECG, clinical blood
chemistry, blood pressure…)♦ number of volunteers depending on variability; at least
12 (EU: healthy, 18-55y; FDA: both sexes, > 18y) ♦ Randomisation
objective: minimising interindividual variability in order to detect product differences!
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 21
Study SubjectsStudy Subjects
Selection of subjects
Safe contraception for women (cave: interferences of contraceptives with investigative drug excluded?)
Phenotyping of volunteers (cave: possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 22
Study SubjectsStudy Subjects
Selection of subjects
participation of healthy volunteers (“in vivo model”) reasonable inclusion and exclusion criteria
(protocol and CRFs) comprehensive verbal and written information volunteers´ insurance reimbursement
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 23
Study SubjectsStudy Subjects
Number of subjects
Required sample size depends on variability either known through reasonable literature or by means of a pilot study
“low” variability: ~ 12 – 20 volunteers “high” variability: ~ 24 – 26 volunteers
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 24
Study SubjectsStudy Subjects
Number of subjects ctd.
Required sample size depends on the expected mean difference between the test and reference formulation
For sample size calculation see literature data (e. g. Eur J Drug Metab Pharmacokinet 30 (2005) 41; J Biopharm Stat 13 (2003) 529; Stat Med 18 (1999) 93 …)
Consideration of possible withdrawals
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 25
Study SubjectsStudy Subjects
Subject withdrawals subject must adhere to study requirements but … they are free to break of at any time definition of “drop-outs” in the protocol (reason,
reimbursement policy, handling of data, follow-up…)
concomitant medication reporting
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 26
Study DesignStudy Design
Crossover-design“latin square” / balanced / randomized
Intra-individual comparison! Parallel group design Replicate design
Volunteer Period 1 Period 2
1 A B
2 B A
… … …
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 27
StandardisationStandardisation
Procedure of drug intake
time of administration (fasted or fed state)
liquid volume
traceability of administrations
cave: e.g. granules, suspensions liquid formulations!
(require ‘method sheet’)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 28
StandardisationStandardisation
Standardised fluid and food intake (time, composition, amount)
Prohibition of alcohol Restriction of xanthins (coffee*, coke, chocolate, chewing
gum, grapefruit)
Standardized posture Restriction of physical activities…
*cave: withdrawal may cause headache
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 29
StandardisationStandardisation
Fasted state
Confinement of subjects at least 10 h prior to drug administration
Last food intake ~10 h prior to drug intake No food or fluids ~2 h prior to drug intake Drug administration with ~150-200 ml xanthine-
free liquid Light standardized meal not before ~4 h post-dose
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 30
StandardisationStandardisation
Fed state
Define time of drug administration and food intake, (e. g. drug intake within 30 min. before, immediately before or after the standardised meal)
High fat meal may serve to investigate the „worst case“ scenario
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 31
Study SamplesStudy Samples
♦ Sampling
♦ number of samples ♦ sampling times (Cmax!)
♦ time of sampling (extrapolated AUC max. 20 %)
♦ wash-out-phase (3 – 4 half-lifes)
knowledge of basic pharmacokinetics of the particular
drug substance is inevitable!
objective: characterisation of ‚drug input‘!(see e.g. sect. 3.1 of the EU guidance 1401/98)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 32
Study SamplesStudy Samples
Number of samples
sufficient to “describe” at least 80 % of total AUC
usually ~12 – 18 samples
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 33
Study SamplesStudy Samples
Sampling times
appr. 3 – 4 to describe drug “input” appr. 3 sampling times around peak concentration appr. 3 – 4 to describe elimination
Minimum!
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 34
Study SamplesStudy Samples
Wash-out-phase
must be long enough to avoid residual concentrations
closely related to the limit of quantitation
metabolites may be considered
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 35
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 36
SamplingSampling
Blood withdrawal equipment (consider bioanalytical method)
Preparation of plasma or serum cooling centrifugation aliquotation labeling freezing transport…
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 37
Bioanalytical MethodBioanalytical Method
The protocol should state
the bioanalytical method/detection the limit of quantitation (1/10 of the expected peak
concentration should be measurable)
the validation concept whether metabolites are to be considered
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 38
CalculationsCalculations
The protocol should state (-among others-)
the transfer of bioanalytical results for biostatistical calculations
the handling of missing data
the handling of digits
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 39
CalculationsCalculations
The protocol should state (-among others-)
calculation procedure/methods
primary characteristics
possible consideration of differences of drug content
acceptance ranges
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 40
Adverse EventsAdverse Events
Definitions and handling/information
Evaluation of seriousness Evaluation of relation to investigative drugs
Treatment (cave: concomitant drug intake should be testet a priori for possible analytical interferences)
Bundesinstitut für Arzneimittel und Medizinprodukte
Pt WHO-consultant 41
Study protocolStudy protocol
?ANY MORE QUESTIONS?